Our research efforts combine molecular target-based discovery with natural products chemistry. Natural products are a source of structural complexity and biological activity that can provide insight on the function of new targets, pathways, or modes of action. They play an important role in dissecting and understanding the intricacies of cancer development, progression, and treatment so continued discovery efforts are highly appropriate for new potential anticancer applications. We work to discover and define the chemistry of compounds that are active in a particular biological system, meaning those that effectively modulate the molecular target of interest, regardless of whether they are new or previously known chemical entities. Thus, appropriate strategies for the selection, prioritization, bioassay-guided fractionation, and dereplication of active extracts were developed to facilitate efficient lead identification. Working in conjunction with our colleagues and collaborators, we successfully undertook studies to identify inhibitors of Activator Protein-1 (AP-1) an oncogenic transcription factor associated with tumor promotion and progression. Our goal was to find compounds that inhibited AP-1 over a broad concentration range before they resulted in cytotoxicity. A total of 29 active compounds were isolated and identified from these extracts with 24 from plant sources, 2 from a marine invertebrate, 2 from a cyanobacterium, and 1 from a fungal extract. The most promising AP-1 inhibitor we obtained was a plant alkaloid known as cephaeline. It is a low micromolar inhibitor of AP-1 that specifically blocked transcriptional activation of AP-1 dependent genes and reduced cellular migration and invasion by a metastatic cancer cell line. A natural product screening effort to discover inhibitors of the multidrug resistance transporter known as Adenosine triphosphate-Binding Cassette protein G2 (ABCG2) provided the marine alkaloid botryllamide G as the lead development compound. Botryllamide G exhibited robust inhibition of ABCG2-mediated drug transport and low cytotoxic activity. It appears to function as a true inhibitor of ABCG2 and not a competitive substrate, that binds to and alters the conformation of the transporter that disrupts its efflux function. A synthesis of botryllamide was developed and it is now undergoing in vivo preclinical development studies. A screening campaign for inhibitors of the oncogenic transcription factor Hypoxia Inducible Factor 2 alpha (HIF-2alpha) identified 31 active extracts that were subjected to bioassay-guided fractionation studies. Fifty five purified compounds were obtained and 33 were provided to our CCR collaborators for ongoing secondary biological evaluation. Natural products that can inhibit the cellular entry or replication of the human immunodeficiency virus (HIV) are also of interest. Novel HIV inhibitory cyclicpeptides have been isolated and identified from a variety of terrestrial plant and marine sources.